This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- OD(ORDR)-101: Pilot projects for prevention, early detection and treatment of rare diseases. Current technology for diagnosis of rare genetic diseases most commonly involves identification of the alteration in DNA. This technology, however, is incomplete as identification of disease causing mutations are missed and the molecular changes that result from the DNA change are poorly understood. This project proposes to approach rare diseases by analyzing what is actually happening in the target disease tissue on a molecular level. Then, in turn, a unique disease signature will be used for diagnostics and the identified molecular pathways involved used to direct targeted therapies. This can be done in the presence or absence of a genetic mutation. This technology is being applied to cancer diagnosis and treatment, and the opportunity exists to apply it to rare diseases. Seven rare colon cancer syndromes whose genes are commonly mutated in sporadic colon cancer progression will be evaluated. This will be accomplished by analyzing RNA from fresh colonic epithelia obtained as biopsies during endoscopy so that alterations in the primary tissue affected by disease can be identified. With this microarray technology, we have identified set of 48 RNA probes that consistently distinguish between control, FAP and AFAP normal appearing colonic tissue and now propose to expand this approach to include additional rare colon cancer syndromes. The three aims of this proposal are to 1) define the unique RNA microarray expression signatures in normal colonic mucosa taken from patients with seven different rare inherited colon cancer syndromes, 2) take the top 20 genes that are differentially regulated in each syndrome to develop a real time quantitative PCR assay for clinical diagnosis and 3) use patient matched normal and neoplastic colonic tissues to identify specific molecular pathways that are altered in each of the syndromes as colonic epithelial cells become hyperproliferative then cancerous and identify molecular targets for treatment. This work is translational, as diagnostic approaches for colon cancer susceptibility will be developed, and additionally, valuable information concerning the genetic and molecular pathways involved in the pathogenesis of colon cancer will be generated. Project Narrative: This project proposes to develop a new approach to diagnose and understand how colon cancer develops and progresses. It will look at differences in the molecular messages in a) normal colon tissue from unaffected people and people with an inherited predisposition to colon cancer and b) differences in molecular message when colon tissue starts to become cancerous. These differences will be the basis of a new diagnostic test and will identify important processes in cancer development that can be targeted with drugs for treatment.